L-PZQ ODT in Schistosoma Infected Children

Merck KGaA, Darmstadt, Germany288 enrolled

Overview

The study would evaluate the safety and efficacy of L-praziquantel orodispersible (L-PZQ ODT) tablets in Schistosoma infected children aged 3 months to 6 years.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

288

Conditions

Schistosomiasis

Interventions

L-PZQ ODT 50 mg/kgDRUG

Participants received single oral dose of L-PZQ ODT 50 mg/Kg on Day 1.

Biltricide®DRUG

Participants received single oral dose of Biltricide® 40 mg/kg on Day 1.

L-PZQ ODT 60 mg/kgDRUG

Participant received single oral dose of L-PZQ ODT 60 mg/kg on Day 1.

Eligibility

Sex: ALLMin age: 3 MonthsMax age: 6 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age of the participant is 4 to 6 years of age (Cohorts 1 and 4), 2 to 3 years of age (Cohorts 2 and 4) 3 to less than 24 months of age (Cohorts 3 and 4) * Participants are; Schistosoma (S.) mansoni positive (Cohorts 1, 2, and 3); diagnosis defined as positive egg counts in stool greater than or equal to ( \>=) 1 egg per 1 occasion) according to World Health Organization (WHO) classification \[1\]: light (1 to 99 eggs per gram of feces), moderate (100 to 399 eggs per gram of feces) and heavy (\>= 400 eggs per gram of feces) infections; S. haematobium positive (Cohort 4); diagnosis defined as positive egg counts in urine (\>= 1 egg per 10 milliliter(mL) urine) according to WHO classification (Prevention and Control of Schistosomiasis and Soil Transmitted Helminthiasis. WHO Technical Report Series No. 912. WHO, Geneva, Switzerland, 2002).light (less than (\<) 50 eggs per 10 mL of urine) and heavy (\>=50 eggs per 10 mL of urine) infections * Participants have a minimum body weight of 8.0 Kilograms (Kg) in 2 to 6 years of age children and 5.0 Kg in 3 months to \< 24 months of age infants and toddlers * Parent's or guardian/legally authorized representative's ability to communicate well with the Investigator and his/her delegate, to understand the protocol requirements and restrictions, and to be willing to have their children comply with the requirements of the entire study, that is: * To be examined by a study physician at screening and 17 to 21 days after treatment * To provide stool samples at screening and 17 to 21 days after treatment * To provide urine samples at screening and 17 to 21 days after treatment * To provide venous blood samples for laboratory assessments * To be housed in the clinic for 12 to 24 hours * To provide venous blood samples for pharmacokinetics (PK) assessments (for participants in the PK subset) * Participants have a minimum hemoglobin level of 10 gram per deciliter Exclusion Criteria: * Participants with following medical conditions are excluded from the study; Findings in the clinical examination and/or laboratory safety examination on the treatment day, that in the opinion of the Investigator constitute a risk or a contraindication for the child's participation in the study or that could interfere with the study objectives, conduct or evaluation. This includes but is not restricted to bacterial or viral infections, such as dysentery, gastroenteritis, ascites, jaundice, etc.; Participants with seizures and/or medical history of seizures and/or other signs of potential central nervous system involvement; Participants with known cysticercosis, or with signs or symptoms (for example: subcutaneous nodules) suggestive of cysticercosis; Participants with an acute infection or other acute illness within the 7 days prior to study screening; Debilitating illness such as tuberculosis, malnutrition, etc. * Treatment with PZQ within the 4 weeks prior to the study screening * Concomitant treatment (within 2 weeks prior to enrollment) with medication that might affect the metabolism of PZQ, such as certain anti epileptics (for example: carbamazepine or phenytoin), glucocorticosteroids (for example: dexamethasone), chloroquine, rifampicin or cimetidine (see Biltricide® Summary of Product Characteristics \[SmPC\]) * Treatment within the 2 weeks prior to the study screening with anti malarial medications * For infants and toddlers being breast fed, treatment of the mothers/wet nurses with PZQ in the 3 days prior to PZQ ODT administration * Participation in any clinical study within 4 weeks prior to administration of PZQ ODT, or anticipated at any time until completion of the End of study visit * Participants with marked increases of the liver enzymes: alanine aminotransferase and/or aspartate aminotransferase above 3 times the upper limit of normal (ULN); total bilirubin level above 1.5 times the ULN * Participants with hepatosplenic schistosomiasis * Fever, defined as temperature above 37.5 degree Celsius axillary or oral mixed S. haematobium and S. mansoni infections

Locations (2)

Universitè de Cocody

Abidjan, Côte d’Ivoire

Kemri Kisumu

Kisumu, Kenya

Outcomes

Primary Outcomes

Cohort 1a and Cohort 1b: Number of Participants With Clinical Cure Determined by Kato-Katz Method

Clinical cure was defined as no parasite egg in the stool at Week 3 as determined by the Kato-Katz method. Number of participants with clinical cure were reported.

Time frame: at Week 3

Secondary Outcomes

Cohort 2 and Cohort 3: Number of Participants With Clinical Cure Determined by Kato-Katz Method

Clinical cure was defined as no parasite egg in the stool at Week 3 as determined by the Kato-Katz method. Number of participants with clinical cure were reported.

Time frame: at Week 3

Cohort 4a and Cohort 4b: Number of Participants With Clinical Cure Determined by Urine Filtration Technique

Clinical cure was defined as no parasite egg in the urine samples at follow up as determined by the urine filtration technique. Number of participants with clinical cure were reported.

Time frame: Week 3 and Week 5

Cohort 1a, Cohort 1b, Cohort 2 and Cohort 3: Egg Reduction Rate (Percent [%]) Determined by Kato-Katz Method

Percentage of reduction in group mean egg count was calculated as relative difference between the post-treatment arithmetic mean egg count and pre-treatment arithmetic mean egg count at baseline count, (pre-treatment mean egg count minus post-treatment mean egg count divided by pre-treatment mean egg count) \*100. Egg counts were determined by the Kato-Katz method.

Time frame: Pre-treatment, Week 3 post-treatment

Cohort 4a and Cohort 4b: Egg Reduction Rate (Percent [%]) Determined by Urine Filtration Technique

Data from ClinicalTrials.gov

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Time frame: Pre-treatment, Weeks 3 and 5 post-treatment

Cohort 1a, Cohort 1b, Cohort 2, and Cohort 3: Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test

Clinical cure is defined as absence of test line in the POC-CCA test cassette (that is no Schistosoma antigens detected). Number of participants with clinical cure were reported.

Time frame: at Week 3

Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-Related TEAEs

Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs were defined as those events with onset dates/time occurring after study intervention administration or events that worsen after study intervention administration. TEAEs included serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention.

Time frame: up to Day 40

Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity According to Qualitative Toxicity Scale

Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported.

Time frame: up to Day 40

Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Change from baseline in hematology parameter: erythrocytes mean corpuscular hemoglobin at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Hematology Parameters: Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration and Hemoglobin

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin. Change from baseline in hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: erythrocytes mean corpuscular volume. Change from baseline in hematology parameter: erythrocytes mean corpuscular volume at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Hematology Parameter: Erythrocytes

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: erythrocytes. Change from baseline in hematology parameter: erythrocytes at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Hematology Parameters: Hematocrit, Lymphocytes/Leukocytes, Mixed Cells/Leukocytes, Neutrophils/Leukocytes

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: hematocrit, lymphocytes/leukocytes, mixed cells/leukocytes, neutrophils/leukocytes. Change from baseline in hematology parameters: hematocrit, lymphocytes/leukocytes, mixed cells/leukocytes, neutrophils/leukocytes at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Hematology Parameters: Leukocytes and Platelets

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: leukocytes and platelets. Change from baseline in hematology parameters: leukocytes and platelets at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Chemistry Parameters: Alanine Aminotransferase and Aspartate Aminotransferase

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameters: Alanine Aminotransferase and Aspartate Aminotransferase. Change from baseline in chemistry parameters: Alanine Aminotransferase and Aspartate Aminotransferase at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Direct Bilirubin

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameters: bilirubin, creatinine and direct bilirubin. Change from baseline in chemistry parameters: bilirubin, creatinine and direct bilirubin at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Chemistry Parameter: C Reactive Protein

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: C reactive protein. Change from baseline in chemistry parameter: C reactive protein at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Chemistry Parameters: Glucose, Urea and Urea Nitrogen

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameters: glucose, urea and urea nitrogen. Change from baseline in chemistry parameters: glucose, urea and urea nitrogen at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Chemistry Parameter: Total Protein

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: total Protein. Change from baseline in chemistry parameter: total Protein at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine

Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameters: specific gravity. Change from baseline in urinalyses parameter: specific gravity Day 1 was reported.

Time frame: Baseline, Day 1

Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine

Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: pH. Change from baseline in urinalyses parameter: pH at Day 1 was reported.

Time frame: Baseline, Day 1

Change From Baseline in Urinalyses Parameter: Urobilinogen

Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: urobilinogen. Change from baseline in urinalyses parameter: urobilinogen at Day 1 were reported.

Time frame: Baseline, Day 1

Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure

Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital signs: diastolic blood pressure and systolic blood pressure at Week 3 were reported.

Time frame: Baseline, Week 3

Change From Baseline in Vital Signs: Pulse Rate

Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital sign: pulse rate at Week 3 was reported.

Time frame: Baseline, Week 3

Change From Baseline in Vital Sign: Respiratory Rate

Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital sign: respiratory rate at Week 3 was reported.

Time frame: Baseline, Week 3

Change From Baseline in Vital Signs: Temperature

Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital sign: temperature at Week 3 was reported.

Time frame: Baseline, Week 3

Number of Participants With Reaction to Study Intervention Administration

Reaction to study intervention administration were recorded to describe tolerability as assessed by nurse/site staff for all children enrolled in the study. Reactions categorized as spitting, crying, diarrheas, sleepiness, abdominal pain, fever, vomiting and other. Number of participants with reaction to study intervention administration reported.

Time frame: Day 1

Cohort 1a, Cohort 1b, Cohort 4a and Cohort 4b: Palatability Assessment Based on Visual Analog Scale (VAS) Score

Palatability of the study intervention was assessed using a human gustatory sensation test (100-millimeter \[mm\] visual analog scale \[VAS\]) incorporating a facial hedonic scale, where lower score (0) indicates "not acceptable/not liked at all" and higher score (100) indicates "very acceptable/liked very much".

Time frame: Day 1

Maximum Observed Plasma Concentration (Cmax) of Praziquantel (PZQ) Enantiomers: R-PZQ and S-PZQ

Cmax was obtained directly from the plasma concentration versus time curve.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose

Time to Reach Maximum Plasma Concentration (Tmax) of Praziquantel (PZQ) Enantiomers: R-PZQ and S-PZQ

Tmax was obtained directly from the plasma concentration versus time curve.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Praziquantel (PZQ) Enantiomers: R-PZQ and S-PZQ

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose